The present invention relates to compounds and pharmaceutical compositions useful as hypocholesterolemic and hypolipidemic agents. More particularly, this invention concerns (1) certain inhibitors of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase) that include a pyridine containing nucleus attached by means of a linker to an HMG-binding domain sidechain, (2) pharmaceutical compositions containing such compounds and (3) a method of lowering blood serum cholesterol levels and modulating blood serum lipid levels employing such pharmaceutical compositions.
U.S. Pat. No. 5,686,433 to Robl-discloses the structure 
wherein:
Am is a binding domain sidechain;
X is a linker;
R1 and R2 are the same or different and are each independently selected from
(i) hydrogen,
(ii) alkyl,
(iii) aryl,
(iv) cycloalkyl,
(v) aralkyl,
(vi) aralkoxy,
(vii) alkenyl,
(viii) cycloalkenyl, and
(ix) heterocyclo (e.g., thienyl, benzodioxolyl);
R3 is selected from
(i) hydrogen,
(ii) lower alkyl,
(iii) aryl,
(iv) cycloalkyl,
(v) alkoxy,
(vi) aralkyl,
(vii) aralkoxy,
(viii) alkenyl,
(ix) cycloalkenyl,
(x) halo-substituted alkyl,
(xi) adamantyl, and
(xii) heterocyclo (e.g., thienyl, benzodioxolyl);
R4 is selected from
(i) hydrogen,
(ii) lower alkyl,
(iii) aryl,
(iv) cycloalkyl,
(v) alkoxy,
(vi) aralkyl,
(vii) aralkoxy,
(viii) alkenyl,
(ix) cycloalkenyl,
(x) adamantyl,
(xi) halogen,
(xii) halo-substituted alkyl (e.g., trifluoromethyl), and
(xiii) heterocyclo (e.g., thienyl, benzodioxolyl); or R3 and R4 taken together can be 
but when Am is 
or a xcex4 lactone thereof, R3 and R4 cannot be (CHxe2x95x90CH)2;
R6 is hydrogen or lower alkyl;
R8 is hydrogen, lower alkyl, alkali metal, or alkaline earth metal;
n is 0 or 1;
p is 3, 4 or 5;
q is 0, 1, 2, or 3; and
r is 0, 1, 2, or 3.
In preferred embodiments (Am) is an HMG-binding domain sidechain having a dihydroxy or a phosphinic acid function.
The phosphinic (or phosphonic when X is CH2xe2x80x94Oxe2x80x94) acid HMG-binding domain sidechain (A1) is 
wherein R5 and R7 are independently selected from hydrogen, lower alkyl, alkali metal ion and alkaline earth metal ion; and R6 is hydrogen or lower alkyl.
The dihydroxy acid binding domain sidechain (A2 is 
wherein R6 is hydrogen or lower alkyl, R8 is hydrogen or lower alkyl in free acid form or in the form of a physiologically acceptable and hydrolyzable ester or xcex4 lactone thereof (i.e., when Am is 
In addition, R8 can be alkali metal ion or alkaline earth metal ion.
A suitable linker (X) is xe2x80x94(CH2)axe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94CH2Oxe2x80x94, wherein O is linked to the phosphorous atom or the aromatic anchor when Am is A1, and wherein O is linked to the aromatic anchor when Am is A2, and wherein xe2x80x9caxe2x80x9d is 1, 2, or 3.
In accordance with the present invention, there are provided certain pyridine-containing compounds that are potent inhibitors of cholesterol biosynthesis by virtue of their ability to inhibit the enzyme 3-methyl-glutaryl-coenzyme A reductase (HMG-CoA reductase).
In particular, in its broadest chemical compound aspect, the present invention provides compounds of the formula 
wherein X is O, S, SO, SO2 or NR7; 
is 0 or 1;
R1 and R2 are the same or different and are independently selected from alkyl, arylalkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl or cycloheteroalkyl;
R3 is H, or lower alkyl or a metal ion (such as an alkali metal or an alkaline earth metal);
R4 is H, halogen, CF3, hydroxy, alkyl, alkoxy, carboxyl, carboxylalkyl-, aminoalkyl, amino, alkanoylamino, aroylamino, cyano, alkoxyCON(R7d)xe2x80x94, R7fR7gNCOxe2x80x94, R7fR7gNCO2xe2x80x94, R7eSO2N(R7d)xe2x80x94, R7fR7gNSO2N(R7d) xe2x80x94, R7eOCO2xe2x80x94 or R7eOCOxe2x80x94;
R7 is H, alkyl, aryl, alkanoyl, aroyl, alkoxycarbonyl, R7aSO2xe2x80x94, R7bR7cNSO2xe2x80x94 or R7bR7cNCOxe2x80x94;
R7a and R7e are the same or different and are independently selected from alkyl, arylalkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl or cycloheteroalkyl,
R7b and R7c, and R7f and R7g, and R7d are the same or different and are independently selected from H, alkyl, arylalkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl or cycloheteroalkyl; or R7b and R7c may be taken together with the nitrogen to which they are attached to form a stable 3 to 8 membered heterocyclic ring, which where applicable, includes a total of 1 to 3 heteroatoms in the ring, which heteroatoms may be N, O or S; or R7f and R7g may be taken together with the nitrogen to which they are attached to form a stable 3 to 8 membered heterocyclic ring which, where applicable, includes a total of 1 to 3 heteroatoms in the ring, which heteroatoms may be N, O or S;
R8 is H or lower alkyl;
R9 and R10 are the same or different and are independently selected from H or alkyl, or where at least one of R9 and R10 is alkyl, R9 and R10 may be taken together with the carbon or carbons to which they are attached to form a 3 to 7 membered carbocyclic ring, which may include a spirocyclic ring;
and  represents a single bond or a double bond (which may be cis or trans);
and including pharmaceutically acceptable salts thereof where R3 is H, esters thereof, prodrug esters thereof, and all stereoisomers thereof.
Preferably, the Z group will be in form of a free acid, a physiologically acceptable and hydrolyzable ester or xcex4 lactone thereof, or an alkali metal salt, alkaline earth metal salt or an amino acid salt.
It is preferred that X is O, SO2 or NR7 where R7 is R7aSO2xe2x80x94.
Preferred are compounds of formula I of the invention wherein
R1 and R2 are independently selected from alkyl, cycloalkyl and aryl;
R4 is H, alkyl or halogen;
X is O; and
n is o.
More preferred are compounds of formula I of the invention wherein R1 is aryl (especially substituted aryl as defined hereinafter);
R2 is alkyl or cycloalkyl;
R4 is H;
R9 and R10 are H;
X is O;
n is o; and
 is a double bond.
Still more preferred are compounds of formula I of the invention wherein
R1 is substituted aryl, preferably 4-fluorophenyl, 4-fluoro-3-methylphenyl or 3,5-dimethylphenyl;
R2 is alkyl or cycloalkyl, preferably isopropyl, t-butyl or cyclopropyl;
R4 is H;
X is O;
n is o;
 is a double bond, preferably xe2x80x9ctransxe2x80x9d; and 
or an alkali or alkaline earth metal salt thereof or an amino acid salt.
Most preferred compounds of formula I of the invention will have the structure 
or an alkali or alkaline earth metal (such as Na, K or Ca) salt thereof, or an amino acid salt (such as arginine), wherein R5 and R6 are the same or different and independently selected from H, halogen and/or alkyl (preferably 4-fluoro, 4-fluoro-3-methyl or 3,5-dimethyl); and
R2 is alkyl or cycloalkyl, preferably isopropyl, t-butyl or cyclopropyl.
In another aspect, the present invention provides pharmaceutical compositions, useful as hypolipidemic or hypocholesterolemic agents, or hypotriglyceridemic agents, or anti-Alzheimer""s agents, or anti-osteoporosis agents as well as other uses as described herein, comprising a hypolipidemic or hypocholesterolemic or hypotriglyceridemic or anti-Alzheimer""s disease or anti-osteoporosis amount, or other therapeutically effective amount (depending upon use) of a compound of formula I in accordance with this invention, in combination with a pharmaceutically acceptable carrier.
In another aspect, the present invention provides a method of inhibiting cholesterol biosynthesis or lowering blood serum cholesterol levels and/or modulating blood serum cholesterol levels such as lowering LDL cholesterol and/or increasing HDL cholesterol, or treating dyslipidemia, mixed dyslipidemia, hyperlipidemia, hypercholesterolemia, hypo xcex1-lipoproteinemia, LDL Pattern B, LDL Pattern A, hyperlipoproteinemia or hypertriglyceridemia, and other aberrations of apolipoprotein B metabolism, or reducing levels of Lp(a), or treating or preventing other cholesterol-related diseases, or treating or preventing or reversing progression of atherosclerosis, or preventing or treating Alzheimer""s disease, or preventing or treating osteoporosis and/or osteopenia, or reducing inflammatory markers such as C-reactive protein, or preventing or treating low grade vascular inflammation, or preventing or treating stroke, or preventing or treating dementia, or preventing and treating coronary heart disease (including primary and secondary prevention of myocardial infarction), or preventing or treating stable and unstable angina, or primary prevention of coronary events, or secondary prevention of cardiovascular events, or preventing or treating peripheral vascular disease, preventing or treating peripheral arterial disease, or preventing or treating acute vascular syndromes, or preventing or reducing the risk of undergoing myocardial revascularization procedures, or preventing or treating microvascular diseases such as nephropathy, neuropathy, retinopathy and nephrotic syndrome or preventing or treating hypertension in a patient in need of such treatment by administering a pharmaceutical composition in accordance with the present invention as defined above.
In addition, in accordance with the present invention, a method is provided for preventing or treating diabetes, especially Type 2 diabetes, and related diseases such as insulin resistance, hyperglycemia, hyperinsulinermia, elevated blood levels of fatty acids or glycerol, obesity, Syndrome X, diabetic complications, dysmetabolic syndrome, and related diseases, and sexual dysfunction, wherein a therapeutically effective amount of a compound of structure I is administered to a patient in need of treatment.
In addition, in accordance with the present invention, a method is provided for preventing and treating malignant lesions (such as ductal carcinoma in situ of the breast and lobular carcinoma in situ of the breast), premalignant lesions (such as fibroadenoma of the breast and prostatic intraepithelial neoplasia (PIN), gastrointestinal malignencies, liposarcomas and various other epithelial tumors (including breast, prostate, colon, ovarian, gastric and lung), cancer-induced asthenia (fatigue), irritable bowel syndrome, Crohn""s disease, gastric ulceritis, and gallstones, and HIV infection, other infectious diseases, drug-induced lipodystrophy, and proliferative diseases such as psoriasis, wherein a therapeutically effective amount of a compound of structure I is administered to a human patient in need of treatment.
In addition, in accordance with the present invention, a method is provided for improving coagulation homeostasis including reducing PAI-1 activity, reducing fibrinogen, and/or reducing platelet aggregation, and/or improving endothelial function, wherein a therapeutically effective amount of a compound of structure I is administered to a patient in need of treatment.
In addition, in accordance with the present invention, a method is provided for treating cholesterol related diseases, diabetes and related diseases, cardiovascular diseases, cerebrovascular diseases as defined above and hereinafter and other diseases as set out above, wherein a therapeutically effective amount of a combination of a compound of structure I and a hypolipidemic agent, and/or lipid modulating agent and/or antidiabetic agent and/or cardiovascular agent, cerebrovascular agent, and/or other type of therapeutic agent, is administered to a patient in need of treatment.
In the above methods of the invention wherein a combination is administered, the compound of structure I will be employed in a weight ratio to the other therapeutic agent (depending upon its mode of operation) within the range from about 0.01:1 to about 500:1, preferably from about 0.5:1 to about 100:1.